The present invention relates to tetrapeptide amides of Formula I which, surprisingly, have been found to possess renin inhibition properties and are thus useful in the treatment of hypertension.
Hypertension is a condition caused by any of a variety of functional abnormalities. For example, hypertension may be related to abnormalities in adrenergic, cholinergic, or neuromuscular interactions; in hormonal balance; or in kidney function, which malfunctions often are caused by abnormalities of the other systems. Treatment with drugs that are intended to act at some receptor site involved in one of the malfunctioning systems has frequently been the basis of therapy. For example, numerous neural receptor blockers are known to act as antihypertensive agents, and diuretics are commonly used to counteract the effects of fluid retention associated with kidney dysfunction. Each of these regimens, however, is associated with side effects often related to inadequate specificity. See generally L. S. Goodman and A. Gilman, eds. The Pharmacological Basis of Therapeutics (New York, 1975), Fifth Edition, Chaps. 26, 27, 28, 30, 33, 39, 40.
The renin-angiotensin system has been implicated in hypertension. See Goodman and Gilman, supra, pp. 630-637. The enzyme renin converts the plasma protein angiotensinogen to the essentially inactive decapeptide angiotensin I, which in turn is proteolytically converted by the so-called "converting enzyme" to the potently vasoactive octapeptide angiotensin II. Various peptidases further hydrolyze angiotensin II to essentially inactive peptide fragments. In addition to regulating blood pressure, angiotensin also stimulates the secretion of aldosterone and thus is intimately involved in regulating the sodium-potassium balance. Thus, inhibition of renin could be an important means of controlling high blood pressure. Certain short-chain peptide analogs of angiotensinogen segments have been reported to inhibit renin activity. K. Poulsen, J. Burton, and E. Haber, Biochemistry, 12, 3877-3882 (1973); J. Burton, K. Poulsen, and E. Haber, Biochemistry, 14, 3892-3898 (1975); J. Burton, R. J. Cody, Jr., A. J. Herd, and E. Haber, Proc. Natl. Acad. Sci. U.S.A., 77, 5476-5479 (1980). Peptide inhibitors of renin activity have also been reported to lower blood pressure in primates. See J. Burton, R. J. Cody, Jr., A. J. Herd, and E. Haber, Proc. Natl. Acad. Sci. U.S.A., 77, 5476-5479 (1980); R. J. Cody, J. Burton, G. Evin, K. Poulsen, J. A. Herd, and E. Haber, Biochem. Biophys. Res. Commun., 97, 230-235 (1980). The present invention provides peptide amides of shorter length which are renin inhibitors and exhibit antihypertensive activity.